The thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are tyrosine-based hormones produced by the thyroid gland that are primarily responsible for regulation of metabolism. Iodine is necessary for the production of T3 and T4. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. The ratio of T4 to T3 released into the blood is roughly 20 to 1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.
The thyronines act on nearly every cell in the body. They act to increase the basal metabolic rate, affect protein synthesis, help regulate long bone growth (synergy with growth hormone) and neuronal maturation, and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness. The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.
Thyroid hormone leads to heat generation in humans. However, the thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals and the moulting behaviour of birds. One effect of administering the thyronamines is a severe drop in body temperature.
Thyroid hormones (T4 and T3) are produced by the follicular cells of the thyroid gland and are regulated by TSH made by the thyrotropes of the anterior pituitary gland. The effects of T4 in vivo are mediated via T3 (T4 is converted to T3 in target tissues). T3 is 3- to 5- fold more active than T4.
Thyroxine (3,5,3',5'-tetraiodothyronine) is produced by follicular cells of the thyroid gland. It is produced as the precursor thyroglobulin (this is not the same as TBG), which is cleaved by enzymes to produce active T4.
The steps in this process are as follows:
- The Na+/I- symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodine ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I- against its concentration gradient.
- I- is moved across the apical membrane into the colloid of the follicle.
- Thyroperoxidase oxidises two I- to form I2. Iodide is non-reactive, and only the more reactive iodine is required for the next step.
- The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.
- Thyroid-stimulating hormone (TSH) released from the pituitary gland binds the TSH receptor ( a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
- The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin.
- These vesicles are then exocytosed, releasing the thyroid hormones.
Thyroxine is produced by attaching iodine atoms to the ring structures of tyrosine molecules. Thyroxine (T4) contains four iodine atoms. Triiodothyronine (T3) is identical to T4, but it has one less iodine atom per molecule.
Iodide is actively absorbed from the bloodstream by a process called iodide trapping. In this process, sodium is cotransported with iodide from the basolateral side of the membrane into the cell and then concentrated in the thyroid follicles to about thirty times its concentration in the blood. Via a reaction with the enzyme thyroperoxidase, iodine is bound to tyrosine residues in the thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). Linking two moieties of DIT produces thyroxine. Combining one particle of MIT and one particle of DIT produces triiodothyronine.
- DIT + MIT → r-T3 (biologically inactive)
- MIT + DIT → triiodothyronine (usually referred to as T3)
- DIT + DIT → thyroxine (referred to as T4)
Proteases digest iodinated thyroglobulin, releasing the hormones T4 and T3, the biologically active agents central to metabolic regulation.
Thyroxine is believed to be a prohormone and a reservoir for the most active and main thyroid hormone T3. T4 is converted as required in the tissues by iodothyronine deiodinase. Deficiency of deiodinase can mimic an iodine deficiency. T3 is more active than T4 and is the final form of the hormone, though it is present in less quantity than T4.
Initiation of production in fetuses 
Thyrotropin-releasing hormone (TRH) is released from hypothalamus by 6 - 8 weeks, and thyroid-stimulating hormone (TSH) secretion from fetal pitutary is evident by 12 weeks of gestation, and fetal production of thyroxine (T4) reaches a clinically significant level at 18–20 weeks. Fetal triiodothyronine (T3) remains low (less than 15 ng/dL) until 30 weeks of gestation, and increases to 50 ng/dL at term. Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism.
Effect of iodine deficiency on thyroid hormone synthesis 
If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormone. The lack of thyroid hormone will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge (the resulting medical condition is called endemic colloid goiter; see goiter). This has the effect of increasing the thyroid's ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.
Circulation and transport 
Plasma transport 
Most of the thyroid hormone circulating in the blood is bound to transport proteins. Only a very small fraction of the circulating hormone is free (unbound) and biologically active, hence measuring concentrations of free thyroid hormones is of great diagnostic value.
|bound to thyroxine-binding globulin (TBG)||70%|
|bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA)||10-15%|
|unbound T4 (fT4)||0.03%|
|unbound T3 (fT3)||0.3%|
Despite being lipophilic, T3 and T4 cross the cell membrane via carrier-mediated transport, which is ATP-dependent. The thyroid hormones function via a well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors.
T1a and T0a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor TAAR1 (TAR1, TA1), a G-protein-coupled receptor located in the cell membrane.
Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.
Membrane transport 
Contrary to common belief, thyroid hormones can not traverse cell membranes in a passive manner like other lipophilic substances. The iodine in o-position makes the phenolic OH-group more acidic, resulting in a negative charge at physiological pH. However, at least 10 different active, energy-dependent and genetic-regulated iodothyronine transporters have been identified in humans. They guarantee that intracellular levels of thyroid hormones are higher than in blood plasma or interstitial fluids.
Intracellular transport 
Thyroxine and triiodothyronine can be measured as free thyroxine and free triiodothyronine, which are indicators of thyroxine and triiodothyronine activities in the body. They can also be measured as total thyroxine and total triiodothyronine, which also depend on the thyroxine and triiodothyronine that is bound to thyroxine-binding globulin. A related parameter is the free thyroxine index, which is total thyroxine multiplied by thyroid hormone uptake, which, in turn, is a measure of the unbound thyroxine-binding globulins.
Effects of thyroxine 
- Increases cardiac output
- Increases heart rate
- Increases ventilation rate
- Increases basal metabolic rate
- Potentiates the effects of catecholamines (i.e. increases sympathetic activity)
- Potentiates brain development
- Thickens endometrium in females
- increase metabolism of proteins and carbohydrates (i.e. they have a catabolic action)
Medical use 
Both T3 and T4 are used to treat thyroid hormone deficiency (hypothyroidism). They are both absorbed well by the gut, so can be given orally. Levothyroxine is the pharmaceutical name (INN) of levothyroxine sodium (T4), which is metabolised more slowly than T3 and hence usually only needs once-daily administration. Natural desiccated thyroid hormones are derived from pig thyroid glands, and are a "natural" hypothyroid treatment containing 20% T3 and traces of T2, T1 and calcitonin. Also available are synthetic combinations of T3/T4 in different ratios (such as liotrix) and pure-T3 medications (INN: liothyronine). Levothyroxine Sodium is usually the first course of treatment tried. Some patients feel they do better on desiccated thyroid hormones; however, this is based on anecdotal evidence and clinical trials have not shown any benefit over the biosynthetic forms.
Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia, which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.
Today most patients are treated with levothyroxine, or a similar synthetic thyroid hormone. However, natural thyroid hormone supplements from the dried thyroids of animals are still available. Natural thyroid hormones have become less popular, due to evidence that varying hormone concentrations in the thyroids of animals before they are slaughtered leads to inconsistent potency and stability. Levothyroxine contains T4 only and is therefore largely ineffective for patients unable to convert T4 to T3. These patients may choose to take natural thyroid hormone as it contains a mixture of T4 and T3, or alternatively supplement with a synthetic T3 treatment. In these cases, synthetic liothyronine is preferred due to the potential differences between drug lots of natural thyroid products. It would be counterintuitive to supplement with T4-only if the patient cannot convert T4 to T3. Some natural thyroid hormone brands are F.D.A. approved, but some are not. Thyroid hormones are generally well tolerated. Thyroid hormones are usually not dangerous for pregnant women or nursing mothers, but should be given under a doctor's supervision. In fact, if a woman who is hypothyroid is left untreated, her baby is at a higher risk for birth defects. When pregnant, a woman with a low functioning thyroid will also need to increase her dosage of thyroid hormone. One exception is that thyroid hormones may aggravate heart conditions, especially in older patients; therefore, doctors may start these patients on a lower dose & work up to avoid risk of heart attack.
Related diseases 
Both excess and deficiency of thyroxine can cause disorders.
- Hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men. Thyrotoxicosis is often used interchangeably with hyperthyroidism, but there are subtle differences. Although thyrotoxicosis also refers to an increase in circulating thyroid hormones, it can be caused by the intake of thyroxine tablets or by an over-active thyroid, whereas hyperthyroidism refers solely to an over-active thyroid.
- Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.
- Clinical depression can sometimes be caused by hypothyroidism. Some research has shown that T3 is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and γ-aminobutyric acid (GABA) in the brain.
Anti-thyroid drugs 
Iodine uptake against a concentration gradient is mediated by a sodium-iodine symporter and is linked to a sodium-potassium ATPase. Perchlorate and thiocyanate are drugs that can compete with iodine at this point. Compounds such as goitrin can reduce thyroid hormone production by interfering with iodine oxidation.
While there are no plants that contain thyroid hormones, there are many plant sources of iodine, if the soil they are grown in contains iodine. Iodine is necessary for the thyroid to produce thyroid hormones. Myxedema may also be treated with synthetic or desiccated natural thyroid hormones.
See also 
- Graves-Basedow disease
- Thyroid gland
- Thyroid-stimulating hormone
- Thyronamines, metabolites of the thyroid hormones that act at the trace amine-associated receptor TAAR1 (TAR1)
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